U.S. patent application number 15/321176 was filed with the patent office on 2017-07-06 for preparation of a solid form of gadobenate dimeglumine.
This patent application is currently assigned to BRACCO IMAGING S.P.A.. The applicant listed for this patent is BRACCO IMAGING S.P.A.. Invention is credited to Pier Lucio ANELLI, Roberta FRETTA, Roberta MAZZON.
Application Number | 20170190719 15/321176 |
Document ID | / |
Family ID | 51260603 |
Filed Date | 2017-07-06 |
United States Patent
Application |
20170190719 |
Kind Code |
A1 |
MAZZON; Roberta ; et
al. |
July 6, 2017 |
PREPARATION OF A SOLID FORM OF GADOBENATE DIMEGLUMINE
Abstract
The present invention relates to a process for the preparation
of a solid form of the gadobenate dimeglumine compound that
comprises obtaining a solution of the said compound in a suitable
solvent A wherein the amount by weight of the water optionally
present in the solution is at most equal to or lower than the
amount by weight of the gadobenate dimeglumine comprised in the
solution and adding the obtained solution to an organic solvent B,
acting as an appropriate antisolvent and favoring the formation of
a solid form of the gadobenate dimeglumine that can be collected by
filtration.
Inventors: |
MAZZON; Roberta; (Volpiano,
IT) ; FRETTA; Roberta; (Collegno, IT) ;
ANELLI; Pier Lucio; (Milano, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRACCO IMAGING S.P.A. |
Milan |
|
IT |
|
|
Assignee: |
BRACCO IMAGING S.P.A.
Milan
IT
|
Family ID: |
51260603 |
Appl. No.: |
15/321176 |
Filed: |
July 20, 2015 |
PCT Filed: |
July 20, 2015 |
PCT NO: |
PCT/EP2015/066512 |
371 Date: |
December 21, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 49/1818 20130101;
C07C 227/40 20130101; A61K 9/0019 20130101; C07F 5/003 20130101;
A61K 49/101 20130101; A61K 9/14 20130101 |
International
Class: |
C07F 5/00 20060101
C07F005/00; A61K 49/18 20060101 A61K049/18; A61K 49/10 20060101
A61K049/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 24, 2014 |
EP |
14178283.9 |
Claims
1. A process for a preparation of a solid form of gadobenate
dimeglumine compound of formula ##STR00002## that comprises: a)
obtaining a solution of the gadobenate dimeglumine in a solvent A
selected from the group consisting of water, aqueous solvents,
organic solvents having a log P value no greater than -0.5, and
mixtures thereof, wherein the amount by weight of the water
optionally present in the solution is no more than the amount by
weight of the gadobenate dimeglumine in the solution; b) adding the
obtained solution of the gadobenate dimeglumine to an antisolvent
B, to obtain the solid form of the gadobenate dimeglumine; and c)
collecting the obtained solid form of the gadobenate
dimeglumine.
2. The process according to claim 1, wherein the antisolvent B is
maintained under stirring and at a temperature below 50.degree.
C.
3. The process according to claim 2, wherein the temperature is
maintained from 0 to 25.degree. C.
4. The process according to claim 3, wherein the step a) comprises
obtaining a solution of the gadobenate dimeglumine in an organic
solvent A having a log P value of from -1.5 to -0.5.
5. The process according to claim 3, wherein the step a) comprises
obtaining a solution of the gadobenate dimeglumine in water or an
aqueous solvent A with a concentration of the gadobenate
dimeglumine at least 50% w/w.
6. The process according to claim 5, wherein the concentration of
the gadobenate dimeglumine in the obtained solution of the
gadobenate dimeglumine solution is of from 53% to 65% (w/w).
7. The process according to claim 4, wherein the step a) comprises
obtaining a solution of the gadobenate dimeglumine by concentrating
an aqueous solution of the gadobenate dimeglumine to a concentrated
solution with a concentration of the gadobenate dimeglumine from
65% (w/w) up to an oily residue, and then diluting said
concentrated solution, or solubilizing said oily residue, with an
amount of the organic solvent A to give the solution of the
gadobenate dimeglumine.
8. The process according to claim 7, wherein the solution of the
gadobenate dimeglumine comprises an amount of water or a residual
aqueous solvent which, by weight, is less than 35% of the amount by
weight of the gadobenate dimeglumine in solution.
9. The process according to claim 4, wherein the organic solvent A
is selected from the group consisting of methanol, DMSO, DMAC, DMF,
ethylene glycol, di-ethylene glycol, and mixtures thereof.
10. The process according to claim 5, wherein step b) comprises
adding the obtained solution of the gadobenate dimeglumine to an
antisolvent B having a log P value ranging from -0.5 to 1.0.
11. The process according to claim 10, wherein the antisolvent B is
maintained under stirring at a temperature of from 0 to 10.degree.
C.
12. The process according to claim 11, wherein the addition of the
solution of the gadobenate dimeglumine to the antisolvent B is
performed in a time ranging from 1 to 8 hours.
13. The process according to claim 10, wherein the antisolvent B is
selected from the group consisting of acetone and 2-propanol.
14. The process according to claim 7, wherein the step b) comprises
adding the obtained solution of the gadobenate dimeglumine to an
antisolvent B having a log P value ranging from -0.5 to about 2.0,
wherein the log P value of the antisolvent B exceeds the log P
value of the solvent A by a value ranging from 0.25 to about
3.5.
15. The process according to claim 14, wherein the antisolvent B is
maintained under stirring and at a temperature from 10 to
25.degree. C.
16. The process according to claim 15, wherein the addition of the
solution of the gadobenate dimeglumine to the antisolvent B is
performed in a time of from 2 to 6 hours.
17. The process according to claim 14, wherein the antisolvent B is
selected from the group consisting of MIBK, 2-butanone,
cyclohexanone, 2-propanol, 2-butanol, ethanol, n-butanol,
2-methyl-1-propanol, t-butyl alcohol, 1-methoxy-2-propanol,
diethylether, methyl t-butylether, diglyme, THF, 2-MeTHF, ethyl
acetate, acetonitrile, and nitromethane.
18. The process according to claim 10, wherein the amount by weight
of the antisolvent B is at least 4 times the amount by weight of
the gadobenate dimeglumine.
19. The process according to claim 10, wherein step c) comprises
collecting by filtration, optionally carried out under an inert
atmosphere, the solid form of the gadobenate dimeglumine obtained
at the step b) of the process to obtain a filtrate, optionally
washing the filtrate with a low-boiling solvent, and drying it.
20. The process according to claim 1, wherein the pair of the
solvent A: the antisolvent B is selected from the group consisting
of water:2-propanol; aqueous solvent:acetone; MeOH:2-propanol;
MeOH:acetone; MeOH:AcOEt; MeOH:Diglyme; DMF:2-propanol;
MeOH:2-butanol; ethylene glycol:2-propanol; MeOH:n-butanol; and
MeOH:MIBK.
21. The process according to claim 1, wherein the step a) of the
process comprises obtaining a solution of the gadobenate
dimeglumine by solubilizing a water insoluble or hardly workable
gummy or glassy solid form of the gadobenate dimeglumine in a
solvent A.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the
preparation of a solid form of the gadobenate dimeglumine. More
particularly, the invention relates to a process using appropriate
dissolution and precipitation solvents enabling to collect the
gadobenate dimeglumine complex salt as a filterable powder which
may be employed, for example, for the preparation of injectable
contrastographic formulations for use in the diagnostic imaging
field.
STATE OF THE ART
[0002] Magnetic Resonance Imaging (MRI) is a renowned diagnostic
imaging technique increasingly used in clinical diagnostics for
growing number of indications.
[0003] The undisputed success of this technique is determined by
the advantages it offers, including a superb temporal and spatial
resolution, the outstanding capacity of differentiating soft
tissues and its safety, due to its non-invasiveness and the absence
of any ionizing radiation, in contrast to, for instance, X-ray, PET
and SPECT.
[0004] The strong expansion of medical MRI has further benefited
from the development of a class of compounds, the MRI contrast
agents, that causes a dramatic variation of the water proton
relaxation rates in the tissues/organs/fluids wherein they
distributes, thereby providing physiological information in
addition to an increase of the anatomical resolution commonly
obtainable in the uncontrasted MRI images.
[0005] Contrast agents for use in the MRI imaging technique
typically include a paramagnetic metal ion, more commonly a
gadolinium ion, which is complexed with an aminopolycarboxylic
chelating ligand, or a suitable derivative thereof.
[0006] Suitable examples of paramagnetic complex compounds that are
in the current clinical use as MRI contrast agents include, for
instance: Gd-DTPA (the gadolinium complex of the
diethylenetriaminepentaacetic acid, N-methylglucamine salt,
marketed as Magnevist.RTM.), Gd-DOTA (gadolinium complex of the
1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid,
N-methylglucamine salt, marketed as DOTAREM.RTM.), and Gd-HPDO3A
(gadolinium complex of the
10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecan-1,4,7-triacetic
acid, marketed as ProHance.RTM.). Besides these agents, that are
designed for a wholly general use, another agent that turned out to
be of particular interest being both suitable for general use, and
the imaging of CNS and hepatic tissue, is GD-BOPTA.
[0007] The dimeglumine salt of the Gd-BOPTA (the gadolinium complex
of the
4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-
-13-oic acid, having the formula provided here below, and otherwise
known as gadobenate dimeglumine, the Merck Index, XIII Ed. 2001, Nr
4344), is the active ingredient of the commonly used MRI contrast
agent commercially known as MultiHance.RTM., that is a 0.5 M
aqueous solution of this compound.
##STR00001##
[0008] As contrast agents are commonly administered to human
patients intravenously, in the form of injectable aqueous
formulations, critical issues in their preparation are the purity
degree with which they are isolated and their water solubility.
Indeed, the quality standards fixed by International Authorities
for pharmaceutical compounds are particularly stringent, especially
for drugs intended for injection. Therefore, the preparation of a
contrast agent in a pure, stable, and convenient physical form
represents, in the most of the cases, the most challenging and
crucial point that has to be addressed by any manufacturer.
[0009] To this extent, a suitable physical form should be, for
instance, the one allowing a reliable and practical recovering of
the intended compound in the final form, ready for use in in vivo
applications, without need of further purification or formulation
steps, and which can also be safely stored for prolonged times.
However, whenever possible, a water soluble solid form of the
chemical product, which is most easily purified and stored, is
generally preferred.
[0010] The preparation of the active ingredient of MultiHance has
been described e.g. in EP0230893 and EP2503990. In more details,
the gadobenate dimeglumine complex is obtained in an aqueous
solution by reaction of the ligand BOPTA with a gadolinium salt,
e.g. halide or acetate, or with the metal oxide Gd.sub.2O.sub.3, in
the presence of N-methyl-D-glucamine (otherwise known as
meglumine).
[0011] Attempts to isolate this contrast agent as a filterable
powder by means of traditional techniques such as crystallization,
solvent evaporation or lyophilisation have not been successful
leading, rather, to the formation of oily products gummy, or
sticky, or glassy solids that, besides being unsuitable for an
industrial use, often lack the necessary water solubility.
[0012] A known process to get this MRI contrast agent in a water
soluble solid form is one making use of the spray-drying technique
as disclosed in EP2503990. The solid gadobenate dimeglumine
collected by spray-drying displays a good water solubility and
wettability and, in general, good handling properties such as, for
instance, good flowability, stability, low hygroscopicity and low
electrostaticity.
[0013] In a comparative example disclosed in EP2503990 (reproduced
in Example 12 of the experimental section herein), an unsuccessful
attempt to isolate the compound by precipitation is described,
namely by adding an aqueous solution of gadobenate dimeglumine (43%
w/w) to propanol solvent.
[0014] Crystallization techniques by using "antisolvents" are
described, for instance, by Tung, H.; Paul, L. E.; Midler, M.; Mc
Cauley, J. A.; Crystallization of organic compounds, Chapter 9,
John Wiley & Sons, 2009.
SUMMARY OF THE INVENTION
[0015] We have now unexpectedly found that gadobenate dimeglumine
can be obtained in a solid and conveniently filterable physical
form by the use of appropriate dissolution and precipitation
solvents and operative conditions.
[0016] In particular we have observed that when a solution of
gadobenate dimeglumine in a highly polar solvent is added to an
organic solvent, acting as an antisolvent, the formation of solid
particles of the complex is observed, that can be filtered and
dried to obtain the gadobenate dimeglumine compound in the desired
solid form with high yields and in a reliable way.
[0017] Accordingly, present invention generally relates to a
process for the preparation of a solid form of the gadobenate
dimeglumine compound that, essentially, comprises: [0018] a)
obtaining a solution of said compound in a suitable solvent A,
[0019] b) adding the obtained solution to an organic solvent B
acting as an antisolvent, thus inducing the formation of a solid
form of the concerned gadobenate dimeglumine compound which
precipitates, [0020] c) collecting the obtained solid
precipitate.
[0021] According to another aspect, the invention relates to the
gadobenate dimeglumine in the solid form obtained with the
precipitation process of the present invention. The solid form of
the gadobenate dimeglumine collected with the process of the
invention is a filterable, water soluble, white powder having an
average particle size comprised from about 1 .mu.m to about 300
.mu.m, even more preferably from about 5 to 100 .mu.m.
[0022] The process of the present invention leads to the isolation
of the gadobenate compound that, advantageously, complies with the
quality standards fixed by International Authorities for
pharmaceutical compounds.
[0023] In addition, advantageously, the solid form of the
Gd-BOPTA-Dimeglumine isolated with the process of the present
invention is optimally water soluble and, once collected, can
conveniently be stored ready for use in the preparation of the
MultiHance.RTM. formulation by simple dissolution of the collected
solid compound in the proper amount of a pharmaceutically
acceptable aqueous solution, including, for instance, sterile water
for injections (WFI), thereby consenting a convenient
simplification of the manufacturing step of the marketed
formulation.
DETAILED DESCRIPTION OF THE INVENTION
[0024] Suitable solvents A for the use of the invention, namely for
preparing a solution of the gadobenate dimeglumine according to the
step a) of the proposed process, include highly polar solvents,
preferably selected from water, aqueous solvents including saline
solutions, highly polar organic solvents, and suitable mixtures
thereof. In this regard, the role assumed by the amount of water,
or aqueous solvent, which may be present in the solution of
gadobenate dimeglumine is particularly relevant. Indeed,
water-containing solutions of gadobenate dimeglumine according to
the invention, namely allowing precipitation of a solid form of the
complex compound, include an amount by weight of the gadobenate
compound at least equal to or, preferably, exceeding the amount (by
weight) of the water optionally present in the solution. In other
words, the amount by weight of water optionally present in the
solution is at most equal to or, preferably, is lower than the
amount by weight of the gadobenate dimeglumine in solution.
[0025] On the other side, appropriate antisolvents according to the
present invention, herein identified as antisolvents B or as
solvent B acting as antisolvent, are, for instance, selected from
organic solvents of moderate polarity that are miscible with the
corresponding solvents A.
[0026] To this extent, and unless otherwise provided, with the
expression "antisolvent" (or precipitation solvent, or co-solvent,
as herein used interchangeably) as used herein in particular with
reference to the solvent B, otherwise identified as "solvent B
acting as antisolvent" or "antisolvent B", we refer to a liquid or
solvent miscible with the solvent (or solvent mixture) A in which
the gadobenate dimeglumine is suitably solubilized, that acts by
decreasing the solubility of this compound in the resulting
mixture, (i.e. the mixture obtained by addition of the solution of
the gadobenate dimeglumine in the solvent A to the solvent B), thus
inducing the formation of a solid precipitate of this same compound
that can be isolated by filtration (see for instance, formerly
cited Tung, H.; Paul, L. E.; Midler, M.; Mc Cauley, J. A.
Crystallization of organic compounds, John Wiley & Sons,
2009).
[0027] Thus, on the one side antisolvent B shall be capable of
being admixed (essentially without phase separation) with solvent A
while, on the other side, it shall be able, once admixed with the
solution of gadobenate dimeglumine in a solvent A, to promote a
substantially quantitative precipitation of gadobenate dimeglumine
as a filterable solid, preferably higher than 70%, more preferably
than 80% and, most preferably, greater than 90% of the of the
gadobenate in solution.
[0028] Appropriate selection of organic solvents A and antisolvents
B for the use of the present invention may be based on their
octanol-water partition coefficient (or partition constant or
partition ratio, as alternatively used in the relevant art and
herein used interchangeably), typically expressed as log P.
[0029] Octanol-water partition coefficient P is a well-known
parameter which is widely used in the relevant chemical field for
instance for estimating how hydrophilic or hydrophobic a chemical
substance is. The value of the octanol/water partition coefficient,
expressed as log P, of a wide number of organic substances,
including the majority of the commonly used organic solvents has
already been determined, and tables with measured log P values are,
for instance, available from common Handbooks of Chemistry and
Physics. (For more details on the partition coefficient P, its
meaning and its determination, as well as tables listing
octanol-water partition coefficients of a wide number of organic
compounds, including organic solvents see, for instance, the CRC
Handbook of Chemistry and Physic, 82 Edition, 2001-2002, from page
16-43 to 16-47, and the cited literature).
[0030] Organic solvents A for the use of the present invention may
be selected among those having a log P value equal to, or less
than, -0.5, more preferably ranging from -1.5 to -0.50 and, most
preferably, from about -1.10 to -0.5, or suitable mixtures
thereof.
[0031] Non-limiting examples of these solvents include, for
instance, methanol (log P=-0.74), DMAC (log P=-0.77), DMF (log
P=-1.01), DMSO (log P=-1.35), glycols such as, for instance,
ethylene glycol (log P=-1.36) and diethylene glycol (log P=-1.47)
and suitable mixtures or aqueous mixtures thereof. Among them,
particularly preferred for the use of the invention is the
methanol, or aqueous mixtures thereof. (With reference to log P
values listed above, or elsewhere in the description see, for
instance, the octanol/water partition coefficient tables provided
by formerly cited CRC Handbook or provided by the US National
library of Medicine, for instance available at the web site
http://chem.sis.nlm.nih.gov/chemidplus).
[0032] Appropriate antisolvents B for the use of the present
invention include organic solvents miscible with the elected
solvent A, typically having a log P value higher than -0.5,
preferably comprised from -0.5 to about 2.0, more preferably, from
-0.5 to 1.5 and, most preferably, from -0.5 to 1.0. In particular,
when the elected solvent A for the use of the invention is an
aqueous solvent, antisolvents B are preferably selected from those
having lower log P values, for instance ranging from -0.5 to 1.0,
and, preferably, from -0.5 to 0.5.
[0033] On the other side, when solvent A is an organic solvent, or
a mixture thereof as above said (including with water), appropriate
antisolvent B for the use of the invention is preferably selected
from those having log P values exceeding that of the used organic
solvent A (or that of the solvent in the mixture having higher log
P) of at least 0.25 and, preferably, of at least 0.5. A difference
between the two log P values not higher than about 3.5 is, however,
preferred, in order not to jeopardize the solvent and antisolvent
miscibility required by the process of the present invention. In
other words, when both the solvent A and the antisolvent B
according to the invention comprise organic solvents, the
difference (or delta, as herein used interchangeably) between the
respective log P values (in case of mixtures, the highest for
solvent A mixture and the lowest value for solvent B mixture) is a
number ranging, for instance, from 0.25 to about 3.5, preferably
from 0.5 to 3 and, more preferably, from 0.5 to 2.
[0034] From all the foregoing, non-limiting examples of
antisolvents B according to the invention include, for instance,
ketones such as acetone (log P=-0.24), methyl isobutyl ketone
(MIBK) (log P=0.56), 2-butanone (log P=0.29) and cyclohexanone (log
P=0.81); C.sub.2-C.sub.5 alcohols such as 2-propanol (log P=0.05),
2-butanol (log P=0.65), ethanol (log P=-0.30), n-butanol (log
P=0.84), 2-methyl-1-propanol (log P=0.76), 1-methoxy-2-propanol
(log P=-0.437) and t-butyl alcohol (log P=0.35); ether such as
diethylether (log P=0.89), methyl t-butylether (log P=0.94),
diethylene glycol dimethyl ether (diglyme) (log P=-0.36),
tetrahydrofurane (THF) (log P=0.46) and 2-MeTHF (log P=1.85);
esters such as ethyl acetate (EtAcO) (log P=0.73), as well as
organic solvents such as acetonitrile (log P=-0.34) and
nitromethane (log P=-0.33).
[0035] Preferred, among them, are MIBK, ethyl acetate, 2-butanol,
diglyme, acetone and 2-propanol, the last two being especially
preferred when the starting solution of the gadobenate dimeglumine
is obtained in an aqueous solvent A.
[0036] Table 1 in the Experimental Section comprises some
representative, not limiting examples of organic solvents A
(vertical column, on the left side of the table) and antisolvents B
(top row in the table) according to the invention and corresponding
log P values. At the intersection (between solvent line and
antisolvent column) the table shows the value of the delta between
the two log P values calculated for the concerned pair of organic
solvent A: antisolvent B.
[0037] An object of the present invention, therefore, concerns a
process for the preparation of a solid form of the gadobenate
dimeglumine compound of the above formula (II) that comprises the
main steps of: [0038] a) obtaining a solution of the gadobenate
dimeglumine in a solvent A selected from water, aqueous solvents,
organic solvents having a log P value equal to or less than -0.5
and suitable mixtures or aqueous mixture thereof, wherein the
amount by weight of the water optionally present in the solution is
at most equal to or lower than the amount by weight of the
gadobenate compound comprised in the solution; [0039] b) adding the
obtained solution to an appropriate organic solvent B acting as
antisolvent, to achieve the formation of a solid form of the
gadobenate dimeglumine; [0040] c) collecting the obtained solid
form of the gadobenate dimeglumine.
[0041] According to the proposed process, a solution of the
gadobenate dimeglumine compound is first obtained in a solvent A,
as above set forth.
[0042] To this extent, the concentration of the gadobenate in the
obtained solution can suitably vary from 1% to an upper limit
determined based on the gadobenate dimeglumine solubility in the
elected solvent, or solvents mixture, and reaching a value up to
about 70%, for instance when the solvent A is water or an aqueous
solvent such as, for instance, a saline solution, in which the
gadobenate compound has a higher solubility. Higher concentrations
(of the gadobenate compound in the solvent A), for instance of at
least 10% or, preferably, equal to or higher than 20%, are,
however, preferred for the use of the invention, conveniently
reducing organic solvent waste.
[0043] To this extent, the starting solution of the gadobenate
dimeglumine compound in the solvent A can be suitably obtained at a
temperature lower than 100.degree. C. and, for instance, comprised
from 20.degree. C. to 100.degree. C., wherein the use of higher
temperature, for instance preferably comprised from 35.degree. C.
up to about 85.degree. C., allows for more concentrated starting
solutions.
[0044] According to one preferred embodiment, the process of the
invention comprises obtaining a suitable solution of the gadobenate
dimeglumine in water or an aqueous solvent A. To this extent, and
as formerly discussed, the concentration of said solution is at
least 50% w/w, that is to say a solution where the amount by weight
of the gadobenate compound is at least equal to that of the water
in the solution, thereby counteracting the high solubility and
hygroscopicity of this compound in an aqueous medium, which might
affect the precipitation of the solid form of the complex
compound.
[0045] More particularly, according to one practical
implementation, the step a) of the process of the invention
comprises obtaining an aqueous solution of the gadobenate
dimeglumine by reacting the chelating ligand BOPTA with gadolinium
oxide (Gd.sub.2O.sub.3), in water and in the presence of meglumine,
at a reaction temperature for instance from 40.degree. C. to
100.degree. C. and, preferably, of about 80.degree. C., and then,
optionally, suitably concentrating the obtained solution.
Alternatively, the aqueous solution of the gadobenate dimeglumine
first obtained according to the step a) of the proposed process is
derived from the industrial process for the preparation of this
complex compound. To this extent, the concentration of said
industrially obtained gadobenate dimeglumine solution is then
adjusted at a desired value, preferably by partial evaporation of
water, which can be performed according to conventional methods, up
to a final concentration of at least 50% w/w, as said, preferably
ranging from 53% to 65% and, more preferably, from 60% to 65%
w/w.
[0046] According to an alternative embodiment, the step a) of the
process of the invention comprises obtaining a solution of the
gadobenate dimeglumine in an organic solvent A.
[0047] To this extent, the aqueous solution of the gadobenate
dimeglumine, for instance obtained from the industrial process for
the preparation of the gadobenate dimeglumine complex compound, is
treated to remove the water solvent, typically by concentration
under vacuum or distillation, to a final concentration for instance
higher than 65% (w/w) and up to an oily residue, or, alternatively,
by lyophilization of the industrial solution, and the obtained
residue is then diluted, or solubilized, depending on the case,
with the appropriate amount of an organic solvent A leading to an
organic solution of the gadobenate dimeglumine of the desired
concentration. Said concentration is at least about 5% w/w and,
preferably, higher than 10%, more preferably higher than 15%, and
most preferably higher than 20% up to an upper limit which depends
on the solubility of the gadobenate dimeglumine in the elected
solvent A, and reaching, for instance, a value of about 50% (w/w)
in preferred organic solvents where the gadobenate shows an
increased solubility.
[0048] For example, when methanol is used as the solvent A,
according to one of the preferred embodiments of the instant
invention, a starting solution of the gadobenate compound is
obtained in this solvent with a concentration ranging from 25% to
about 50% and, more preferably, 35% to about 50%, being the above
upper limit consistent with the solubility of the gadobenate
complex in this solvent. When, instead, organic solvents A are used
in which the gadobenate dimeglumine is less soluble, as is the
case, for instance, of DMF, then less concentrated gadobenate
solutions, e.g. ranging from about 5% to about 15% (w/w), can also
be used profitably, without incurring in unwanted reductions of the
precipitation yield.
[0049] The organic solution of the gadobenate compound obtained
according to the step a) of the process of the invention may,
optionally, include an amount of water, for instance an aqueous
solvent residue. To this extent, the amount (by weight) of water or
residual aqueous solvent in the organic solution is herein
conveniently expressed by reference to the amount (by weight) of
gadobenate in solution, as per cent of the amount by weight of the
gadobenate dimeglumine compound, according to the following
equation
% water amount = 100 amount of water ( g ) amount of gadobenate
dimeglumine ( g ) ##EQU00001##
[0050] According to the foregoing, the amount of water in the
organic solution according to the invention is less than about 55%
and, preferably less than 35% of the amount by weight of the
gadobenate dimeglumine in solution; more preferably the water
amount in solution is from 5% to 20% and, particularly preferably,
from 8% to 15% of the amount by weight of the gadobenate complex in
solution.
[0051] In a still alternative embodiment of the invention, the step
a) of the process comprises obtaining a suitable starting solution
of the gadobenate dimeglumine by solubilization of solid gadobenate
compound, for instance recovered by a spray drying procedure, or,
alternatively, by lyophilization of an aqueous solution of the
product, in the proper amount of the selected solvent A leading to
a gadobenate solution of the desired concentration.
[0052] Once prepared, the collected solution of the gadobenate
dimeglumine in the solvent A is added to the appropriate
antisolvent B.
[0053] In particular, according to the step b) of the process of
the present invention, the solution of the gadobenate dimeglumine
deriving from step a) is slowly added to a suitable antisolvent B
maintained, for all the time of the addition, under appropriate
stirring and temperature conditions, thus causing the progressive
precipitation of a filterable solid form of the said concerned
contrast agent.
[0054] In this regard, the amount by weight of antisolvent B that
is used according to the process of the invention preferably
exceeds that of the gadobenate dimeglumine compound within the
solution (of this contrast agent) deriving from the step a) of the
process. In particular, the amount by weight of the antisolvent B
is preferably at least 4 times higher, for example from 4 to 100
times, preferably from 4 to 50 and, more preferably, from 4 to 20
times the amount (by weight) of the gadobenate dimeglumine in
solution.
[0055] According to the process of the present invention, the
addition of the gadobenate solution to the appropriate antisolvent
is preferably performed gradually over the time, for instance in
portion or, preferably, dropwise, or with a constant flow rate, by
operating according to conventional means, in a time taking up to
10 hours, preferably from 1 to 8 hours, and, more preferably,
ranging from 2 to 6 hours. Throughout the said addition period, the
antisolvent B is properly maintained under vigorous stirring and at
a suitable temperature, for instance below 50.degree. C.
[0056] More particularly, according to a preferred embodiment, the
step b) of the process of the present invention comprises adding,
over an appropriate period of time, as detailed above, the solution
of the gadobenate dimeglumine (in the solvent A) to the appropriate
antisolvent B. Antisolvent B is preferably kept (for the entire
time of the addition) under vigorous stirring. The addition mixture
(including the antisolvent B and the added solution of the
gadobenate dimeglumine) is also preferably kept at a controlled
temperature ranging, for instance, from 0 to 50.degree. C.,
preferably from 0 to 25.degree. C., more preferably from 0 to
10.degree. C. and, even more preferably, from 0 to 5.degree. C.,
though temperatures below 0.degree. C., e.g. preferably comprised
from 0 and -10.degree. C., can profitably be used when the solvent
A is an organic solvent.
[0057] The expression "vigorous stirring as used herein, and unless
otherwise indicated, comprises a stirring of at least 200 rpm
(revolutions per minute) and, preferably, from 250 to 450 rpm, when
operating on a pre-industrial or pilot scale, or a corresponding
vigorous stirring obtainable with industrial equipment, when
operating on an industrial scale.
[0058] In practical terms, according to one preferred practical
implementation of the proposed process, a starting aqueous solution
of the gadobenate compound, for instance obtained by suitable
concentration of the aqueous solution from the industrial process
for the preparation of the gadobenate dimeglumine complex compound,
is added over a time period of at least about 4 hours and,
preferably, of from 4 to 8 hours, to an appropriate antisolvent
suitably stirred and cooled (for the whole addition time) at a
temperature from 0 to 10.degree. C. and, preferably, from 0 to
5.degree. C.
[0059] When, instead, a solution of the gadobenate dimeglumine is
obtained in an organic solvent A, according to a particularly
preferred embodiment of the process of the invention, the almost
quantitative precipitation of solid gadobenate is advantageously
obtained over a period of time ranging, preferably, from 2 to 6
hours, and, more preferably, in less than 4 hours, considering the
time of addition of the gadobenate solution in the antisolvent B
kept, the latter, under stirring at temperatures close to or lower
than room temperature, for example ranging from 10.degree. C. to
25.degree. C.
[0060] From all the foregoing, by applying the operating conditions
set forth by the process of the present invention, the progressive
precipitation of the solid form of the gadobenate dimeglumine is
obtained, that can thus be collected by filtration, according to
the step c) of the process of the invention.
[0061] To this extent, for instance, the obtained solid gadobenate
can be suitably collected immediately, i.e. at the end of the
addition, or, alternatively, the precipitate can be maintained
under stirring, for instance for a few hours, at the same or even
lower temperature, for example from 0 to 10.degree. C., as
described in better details in the experiment section below, and
then filtered to give the desired solid form of the contrast agent
with good yield and in a reliable way.
[0062] More particularly, the step c) of the process of the
invention comprises collecting, by filtration, the gadobenate
dimeglumine in solid form obtained by precipitation at the step b)
of the process; the collected precipitate is preferably washed with
antisolvent B and then dried, for instance under reduced pressure,
to obtain a white solid powdery residue.
[0063] Alternatively, the wet filtrate can be properly washed, or
further washed, with a more volatile solvent, typically a low
boiling solvent such as acetone or a suitable ether, as better
detailed in the experimental section that follows, thereby
obtaining by filtration and appropriate drying step a solid form of
the gadobenate dimeglumine with a minimized amount of residual
water or organic solvent.
[0064] According to one embodiment of the invention, the step c) of
the instant process is carried out under normal air conditions or,
according to an alternative embodiment, it may be suitably carried
out under an inert atmosphere.
[0065] To this extent, working conditions using an inert atmosphere
are particularly preferred when the solvent A is water or an
aqueous solvent such as, for instance, the one in which is
dissolved the gadobenate dimeglumine directly obtained by the
industrial process for the preparation of the Gd-BOPTA complex
compound. In this case, in fact, a hygroscopic wet solid may be
obtained, which is preferably filtered, washed and dried under an
inert atmosphere, typically under nitrogen or argon atmosphere.
[0066] From all the foregoing, the process of the present invention
allows to conveniently isolate and collect the meglumine salt of
the gadobenate complex with high yields and in a substantially pure
solid form, i.e. with negligible amounts of side products or
unreacted materials, such as the free chelating agent, or the free
metal.
[0067] Advantageously, moreover, the process of the present
invention allows to recover gadobenate dimeglumine in a workable,
water-soluble solid form, suitable for the preparation of
pharmaceutical injectable compositions of the gadobenate complex
compound, from substantially any production batch of the product.
For instance, gadobenate meglumine may be recovered from production
batches which may be obtained, for accidental reasons or technical
or procedural problems, in a undesirable glassy or rubbery form,
or, in any case, in a form which is not highly soluble in water,
and thus unsuitable for the preparation of the injectable contrast
agent composition.
[0068] To this extent, Examples 11, 12 and 13 of the Experimental
Section below show that a water-soluble and suitably workable solid
form of the GD-BOPTA-dimeglumine can conveniently be recovered by
using the process of the invention from a gummy solid recovered
according to the comparative example 2C of EP2503990, or a glassy
or unworkable solid form of the complex, for instance formed during
an altered preparation of the contrast agent.
[0069] Therefore, in a further embodiment, the present invention
relates to a process for the recovery of gadobenate dimeglumine in
a water soluble and suitably workable solid form, that comprises
obtaining a solution of the gadobenate dimeglumine according to the
step a) of the process by solubilizing a water insoluble or hardly
workable form of said complex compound in a suitable solvent A.
[0070] The invention further relates to the solid form of the
gadobenate dimeglumine directly obtained by the process of the
invention, as widely described above.
[0071] To this extent, the solid form of the gadobenate dimeglumine
obtained according to the invention is a stable, water soluble
powdered solid having a particle size from 1 .mu.m to 300 .mu.m,
and preferably comprised from 5 .mu.m to 100 .mu.m.
[0072] As formerly discussed, the complex compound collected with
the proposed process is endowed with a good stability, favorable
workability and, especially, optimal water solubility. Indeed, it
has proven to possess optimal water-dissolution characteristics,
requiring less than 1 mL of water for 1 g of product at
25-30.degree. C., to have complete ready dissolution in less than
five minutes.
[0073] Moreover, after its isolation, the collected solid product
can conveniently be stored for long periods of time, for instance
up to 2 years when properly stored, (i.e. under inert atmosphere)
in a form that is ready for use in the preparation of the
MultiHance.RTM. formulation, by simple dissolution of the solid
compound in the proper amount of a pharmaceutically acceptable
aqueous solution, such as, for instance, the sterile water for
injections (WFI) or any another proper aqueous medium, according to
procedures commonly employed in the art.
[0074] For instance, the solid form of the Gadobenate Dimeglumine
collected at the step c) of the process may be stored and
transported without need of specific temperature control and in
particular it may be supplied to hospitals and physicians for
on-site formulation into a ready-to-use administrable solution
without requiring such users to have special storage
facilities.
[0075] Preferably, in such a case it can be supplied in the form of
a two-component kit, which can include two separate containers or a
dual-chamber container. In the former case a first container
contains the solid form of the Gadobenate and the second container
contains a physiologically acceptable carrier. Examples of suitable
carriers include, for instance, water, typically sterile, pyrogens
free water (which may also be indicated as water for injection),
aqueous solution such as saline solution (which may advantageously
be balanced so that the final product for injections is not
hypotonic), or aqueous solutions of one or more tonicity adjusting
substances such as salts or sugars, sugar alcohol, glycols or other
non-ionic polyol materials (e.g. glucose, sucrose, glycerol,
glycols and the like).
[0076] Preferably the container is a conventional septum-sealed
vial, wherein the vial containing the solid product of step c) is
sealed with a septum through which the carrier liquid stored in the
second container may be injected using an optionally prefilled
syringe. In such a case, a syringe may be used as the convenient
container of the second component is also used then for injecting
the contrast agent.
[0077] In the latter case, preferably the dual-chamber container is
a dual-chamber syringe and once the solid form of the Gadobenate
dimeglumine has been reconstituted and then suitably mixed or
gently shaken, the container can be used directly for injecting the
contrast agent.
[0078] Therefore, besides providing for a solid pure product in a
reliable way, with good yields, the process of the invention allows
to conveniently simplify and fully standardize the preparation of
MultiHance.RTM. marketed formulation.
[0079] Interestingly, moreover, the proposed process allows to
achieve all these results using conventional, multipurpose
equipment, i.e. without requiring specifically devoted instruments
or technology, such as, for instance, a spray-dryer, thereby making
the process of the present invention advantageously flexible and
versatile.
[0080] From all the above, it will be apparent that the process of
the present invention, comprising obtaining a suitable solution of
the said compound in a solvent A, adding, under stirring and
appropriate temperature conditions, said obtained solution in a
suitable organic antisolvent B, thus inducing the precipitation of
solid particles of the complex compound that are collected by
filtration, washed and dried under reduced pressure and,
optionally, under inert atmosphere, enables the isolation of a
water soluble solid form of the gadobenate dimeglumine which can
conveniently be stored, or packaged as a kit of parts, ready for
use in the simplified and reliable preparation of the
MultiHance.RTM. marketed formulation.
[0081] Noteworthy, the process of the invention may be conveniently
employed even on a large scale, for the preparation of a gadobenate
dimeglumine compound intended for the use as diagnostic agents.
[0082] The following examples of the practice of the present
invention are meant to support the consistency and reliability of
the process of the present invention. However, it should be
understood that the particular embodiments illustrating the present
invention are meant to be illustrative and are in no way limiting
the scope of the invention.
[0083] Experimental Part
EXAMPLE 1
Preparation of an Aqueous Solution of Gadobenate Dimeglumine
[0084] A solution of BOPTA (209.7 g; assay 92%, 0.375 mol) and
N-methyl-D-glutamine (meglumine) (146.4 g; 0.750 mol) in water (240
mL) was added to a suspension of gadolinium oxide (68.85 g; 0.190
mol) in water (210 mL) and the mixture was kept under stirring at
80.degree. C. for about 75 min.
[0085] The mixture was then cooled to room temperature and
filtered, and its pH was adjusted to 6.9-7.0 by addition of
meglumine. The obtained solution (concentration: 0.53 mol/L,
corresponding to about 46% (w/w)) that is adjusted to the desired
value, for instance by concentration under vacuum.
EXAMPLE 2
Preparation of Solid Gadobenate Dimeglumine by Use of an Aqueous
Solvent and 2-Propanol, Respectively as Solvent a and Antisolvent
B
[0086] In a 3 L reactor, equipped with a mechanical stirrer,
2-propanol (1858 g) was added and cooled to 2.degree. C. An aqueous
solution of gadobenate dimeglumine obtained as in the example 1,
then further concentrated (310.2 g, 62.7% w/w, corresponding to an
amount by weight of water of 59.5%, calculated as percent ratio
versus the amount by weight of gadobenate in the solution) and
maintained at room temperature, was added dropwise in 6 h to
2-propanol, kept under strong stirring (300 rpm). The obtained
slurry was stirred at 2.degree. C. for further 16 h. Then it was
filtered in an inert atmosphere and the collected solid was washed
with 2-propanol (450 mL).
[0087] The wet solid was dried for 5 h at 30 mbar 30.degree. C.,
obtaining a white powder (193.8 g; yield 93.4%, calculated on
anhydrous and solvent free basis; loss on drying 6.3%; water
content 3.0%).
EXAMPLE 3
Preparation of Solid Gadobenate Dimeglumine by Use of an Aqueous
Solvent and Acetone, Respectively as Solvent a and Antisolvent
B
[0088] In a 3 L reactor, equipped with a mechanical stirrer,
acetone (1700 g) was added and cooled to 2.degree. C. Then an
aqueous solution of gadobenate dimeglumine (180.0 g; 62.7% w/w),
kept at room temperature, was added dropwise in 6 h, keeping the 3
L reactor under strong stirring (300 rpm). The mixture was stirred
at 2.degree. C. for further 16 h. Then it was filtered in an inert
atmosphere and washed with acetone (700 mL).
[0089] The wet solid was dried for 5 h at 30 mbar 30.degree. C.,
obtaining a white powder (108.6 g; yield 90,1%, calculated on
anhydrous and solvent free basis; loss on drying 6.4%; water
content 3.91%).
EXAMPLE 4
Preparation of Solid Gadobenate Dimeglumine by Use of MeOH and
2-Propanol, Respectively as Solvent A and Antisolvent B
[0090] A gadobenate dimeglumine solution (0.5 M; 350 mL), prepared
according to the procedure described example 1, was concentrated
under reduced pressure (50-70 mbar; 50.degree. C.) to oily residue.
The residue was dissolved in 170 g of MeOH at 40.degree. C.
(concentration of the obtained gadobenate dimeglumine solution:
approximately 48%, water content 14%, calculated as percent ratio
versus the amount by weight of gadobenate in the solution). After
cooling to room temperature the obtained solution was added in 5 h
to a 3 L reactor containing 2-propanol (1500 g), previously cooled
to 2.degree. C.; during the addition the reactor was kept under
stirring (250 rpm). The mixture was stirred at 2.degree. C. for
further 16 h and then was filtered in nitrogen atmosphere; the wet
solid was washed with 2-propanol (500 mL).
[0091] The wet solid was dried for 5 h at 35 mbar and 30.degree.
C., and for 4 h at 8 mbar 40.degree. C., obtaining a white powder
(183.2 g; yield 95.4%, calculated on anhydrous and solvent free
basis; loss on drying 3.60%).
EXAMPLE 5
Preparation of Solid Gadobenate Dimeglumine by Use of MeOH and
Acetone, Respectively as Solvent A and Antisolvent B
[0092] A gadobenate dimeglumine solution (0.5 M; 186.5 mL),
prepared according to the procedure described example 1, was
concentrated under reduced pressure (50-70 mbar; 50.degree. C.) to
oily residue. The residue was dissolved in 140 g of MeOH at
40.degree. C. (concentration of the gadobenate dimeglumine solution
approximately 47%, water content 11%, calculated as percent ratio
versus the amount by weight of gadobenate in the solution). After
cooling to room temperature the obtained solution was added
(addition time: 4 h) to a 1.5 L reactor containing acetone (800 g)
kept at 25.degree. C. and under stirring for the whole time of
addition. The mixture was stirred at 25.degree. C. for further 1 h,
then was filtered and the wet solid was washed with acetone (500
mL).
[0093] The wet solid was dried for 16 h at 35 mbar 40.degree. C.,
obtaining a white powder (109.1 g; yield 98.1% calculated on
anhydrous and solvent free basis; loss on drying 11.3%).
[0094] The solid was further dried at 60.degree. C. and 10 mbar for
another 40 h to reach a loss on drying of 4.6%
EXAMPLE 6
Preparation of Solid Gadobenate Dimeglumine by Use of MeOH and
Ethyl Acetate, Respectively as Solvent A and Antisolvent B
[0095] A 1.5 L reactor, equipped with a mechanical stirrer, was
loaded with ethyl acetate (800 g) and cooled to 5.degree. C. Then a
gadobenate dimeglumine solution in methanol (220 g; 45% w/w; water
content 3.52%, calculated as percent ratio versus the amount by
weight of gadobenate in the solution), kept at room temperature,
was added, dropwise, in the cooled acetate, in a time of about 6 h.
The obtained mixture was stirred at 5.degree. C. for 1 additional
hour, then filtered and washed with ethyl acetate (400 mL).
[0096] The collected wet solid was dried for 16 h at 25 mbar
40.degree. C., obtaining a white powder (103.4 g; quantitative
yield, calculated on anhydrous and solvent free basis; loss on
drying 3.83%).
EXAMPLE 7
Preparation of Solid Gadobenate Dimeglumine by Use of MeOH and
Dyglime, Respectively as Solvent A and Antisolvent B
[0097] In a 2 L reactor, equipped with a mechanical stirrer,
diglyme (800 g) was added and cooled to 10.degree. C. Then
gadobenate dimeglumine solution in methanol (285 g; 35% w/w; water
content 3.42%, calculated as percent ratio versus the amount by
weight of gadobenate in the solution), kept at room temperature,
was added in 3 h, keeping the reactor under strong stirring. The
mixture was stirred at 10.degree. C. for further 2 h, then the
solid was filtered, washed with diglyme (300 mL) and dried for 16 h
at 25 mbar 40.degree. C., and for another 25 h at 60.degree. C. 5
mbar obtaining a white powder (110.9 g; yield 96.4%, calculated on
anhydrous and solvent free basis; loss on drying 12.4%).
[0098] The obtained solid was then further suspended in acetone
(300 g), kept under stirring for 4 h, filtered and dried for 45 h
at 10 mbar 60.degree. C. by obtaining a 96.8 g of a final solid
(yield 98.1, loss on drying 1.5%; water content 0.92%).
EXAMPLE 8
Preparation of Solid Gadobenate Dimeglumine by Use of DMF and
2-Propanol, Respectively as Solvent A and Antisolvent B
[0099] A gadobenate dimeglumine solution (0.5 M; 150 mL), prepared
according to the procedure described example 1, was partially
concentrated under reduced pressure (90-120 mbar; 50.degree. C.;
distilled water 50 g). The residue was diluted in DMF (610 g) and
the distillation was continued to remove a further amount of water
(25 g). After cooling to room temperature, the obtained solution
(gadobenate dimeglumine concentration 11.0%, water content 36.4%
(calculated as percent ratio versus the amount by weight of
gadobenate in the solution)) was added in 4 h to a 3 L reactor
containing 2-propanol (1000 g), kept under stirring at 5.degree. C.
The mixture was stirred at 5.degree. C. for further 1 h. Then it
was filtered and the wet solid was washed with 2-propanol (500
mL).
[0100] The wet solid was dried for 24 h at 5 mbar 40.degree. C.,
obtaining a white powder (74.3 g; yield 89.6%, calculated on
anhydrous and solvent free basis; loss on drying 4.24%).
EXAMPLE 9
Preparation of Solid Gadobenate Dimeglumine by Use of an Aqueous
Solution of Gadobenate Having a Concentration of 50% (w/w) and
2-Propanol as Antisolvent B
[0101] In a 1.5 L reactor, equipped with a mechanical stirrer,
2-propanol (850 g) was added and cooled to 2.degree. C.
[0102] Then, maintaining the reactor under strong stirring, an
aqueous solution of gadobenate dimeglumine (90.4 g, concentration
50% w/w), kept at room temperature, was added in 3 h; the obtained
suspension was stirred at 2.degree. C. for further 1.5 h.
[0103] Gadobenate dimeglumine initially precipitated as a thin
solid but, at the end of the addition, the precipitate started to
become sticky, forming progressively crusts and lumps.
[0104] The preparation was repeated in the same conditions, with
the only difference that, just finished the addition, the slurry
was filtered immediately, by operating under nitrogen. A slightly
sticky solid was thus obtained, that was washed with acetone (100
g) and dried at 35.degree. C. 20 mbar for 16 h, obtaining a white
coarse powder (31.6 g; yield 69.0%, calculated on anhydrous and
solvent free basis; loss on drying 1.2%; water content 0.7%).
EXAMPLE 10
Preparation of Solid Gadobenate Dimeglumine by Use of an Aqueous
Solution of Gadobenate with a Concentration 53% (w/w) and
2-Propanol as Antisolvent B
[0105] In a 1.5 L reactor, equipped with a mechanical stirrer,
2-propanol (850 g) was added and cooled to 2.degree. C. Then,
maintaining the reactor under strong stirring, an aqueous solution
of gadobenate dimeglumine, prepared as described in example 1 and
further concentrated (102 g; concentration 53.3% w/w), kept at room
temperature, was added in 2.5 h.
[0106] The mixture was stirred at 2.degree. C. for further 1 h. The
solid was filtered and dried at 30.degree. C. 30 mbar for 17 h
(40.7 g; yield 70.9%, calculated on anhydrous and solvent free
basis; loss on drying 5.2%; water content 1.83%).
EXAMPLE 11
Recovery of Water Soluble Gadobenate Dimeglumine from a Glassy,
Water Insoluble Form of the Complex by Using MeOH and 2-Butanol,
Respectively as Solvent A and Antisolvent B
[0107] A gadobenate dimeglumine solution (0.5 M; 172 mL), prepared
according to the procedure described example 1, was lyophilized. A
glassy solid was obtained that was then dissolved with 122 g of
MeOH at 45.degree. C. (gadobenate dimeglumine concentration 40%
w/w; water content 14.6% (calculated as percent ratio versus the
amount by weight of gadobenate in the solution)). The obtained
solution was cooled to 20.degree. C. and then added, in about 3 h,
into 1 L reactor loaded with 2-butanol (726 g) cooled at
10-15.degree. C. and kept under stirring. The mixture was then
stirred at 15.degree. C. for one additional hour, then was filtered
and the wet solid was washed with acetone (250 g).
[0108] The wet solid was dried under vacuum for 18 h at 40.degree.
C., and for 5 h at 60.degree. C. obtaining a white powder (84.3 g;
yield 94.4% calculated on anhydrous and solvent free basis; loss on
drying 1.90%)
EXAMPLE 12
Recovery of Water Soluble Gadobenate Dimeglumine from a Unworkable
Form of the Complex Compound by Using MeOH and Acetone,
Respectively as Solvent A and Antisolvent B.
[0109] Operating according to the conditions reported in EP2503990
comparative example 2C, a gadobenate dimeglumine solution (0.5 M;
100 mL, about 43% w/w) was dropwise added to a reactor containing
2-propanol (2 L) stirred at room temperature; a sticky gummy solid,
forming lumps and crusts on the reactor stirrer and walls, was
obtained. The solvent was removed by decantation and the solid was
dissolved in MeOH (130 g) at 45.degree. C. The obtained solution
was concentrated under reduced pressure (70-90 mbar; 35.degree. C.)
to obtain a final weight of 130.8 g (gadobenate dimeglumine
concentration 40.4% w/w; water content 10.1% (calculated as percent
ratio versus the amount by weight of gadobenate in the
solution).
[0110] The obtained solution was cooled to 25.degree. C. and then
added, in 2 h, to a reactor containing acetone (450 g) kept, during
all the addition time, at 19.degree. C. and under vigorous
stirring. The mixture was kept at 19.degree. C. and under stirring
for additional 4 h, then was filtered and the wet solid was washed
with acetone (150 g).
[0111] The wet solid was dried under vacuum for 17 h at 40.degree.
C., and for 43 h at 60.degree. C. (43.9 g; yield 86.9% calculated
on anhydrous and solvent free basis; loss on drying 4.6%).
EXAMPLE 13
Recovery of Water Soluble Gadobenate Dimeglumine from a
Water-Insoluble Form of the Complex Compound by Using Ethylene
Glycol and 2-Propanol, Respectively as Solvent A and Antisolvent B
and Washing the Collected Wet Solid with Diisopropyl Ether
[0112] A gadobenate dimeglumine solution (0.5 M; 66.3 mL), prepared
according to the procedure described example 1, was lyophilized. A
glassy solid was obtained that was successively dissolved at
45.degree. C. with 61.4 g of ethylene glycol, obtaining 100 g of a
gadobenate dimeglumine solution with concentration of 35.1% w/w and
a residual water content of 10.1% (calculated as percent ratio
versus the amount by weight of gadobenate in the solution).
[0113] In a 1 L reactor, equipped with a mechanical stirrer,
2-propanol (450 g) was added and cooled to 10.degree. C. The
solution of gadobenate dimeglumine in ethylene glycol, kept at room
temperature, was then added in 1 h, keeping the reactor under
strong stirring. The obtained solid precipitate was filtered and
washed with diisopropyl ether (100 g); then the wet panel was
re-suspended with 300 g of diisopropyl ether and kept under
stirring for 2 h. The solid was filtered and dried for 17.5 h at 25
mbar 40.degree. C. (30.76 g; yield 87%, calculated on anhydrous and
solvent free basis; loss on drying 0.7%).
TABLE-US-00001 TABLE 1 ANTISOLVENT B Organic 2- 2- 1-methoxy-
Diethyl 2- n- solvent A Acetone MIBK propanol butanol Diglyme AcOEt
2-propanol THF ether Butanone butanol CH.sub.3CN Log P -0.24 0.56
0.05 0.65 -0.36* 0.73 -0.44 0.46 0.89 0.29 0.84 -0.33 MeOH -0.74
0.5 1.3 0.79 1.39 0.38 1.47 0.30 1.2 1.63 1.03 1.58 0.41 DMF -1.01
0.77 1.57 1.06 1.66 0.65 1.74 0.57 1.47 1.9 1.3 1.85 0.68 DMAC
-0.77 0.53 1.33 0.82 1.42 0.41 1.50 0.33 1.23 1.66 1.06 1.61 0.44
DMSO -1.35 1.11 1.91 1.4 2 0.99 2.08 0.91 1.81 2.24 1.64 2.19 1.02
ETHYLENE -1.36* 1.12 1.92 1.41 2.01 1 2.09 0.92 1.82 2.25 1.65 2.20
1.03 GLYCOL DIETHYLENE -1.47* 1.23 2.03 1.52 2.12 1.11 2.2 1.03
1.93 2.36 1.76 2.31 1.14 GLYCOL
[0114] log P values are from CRC Handbook of Chemistry and Physic,
82 Edition, 2001-2002, from page 16-43 to 16-47, or (labelled with
*) from U.S. National Library of Medicine, by the U.S. National
Institute of Health.
* * * * *
References